Potent and orally active Cav3.1 & Cav3.3 T-type voltage-gated Ca2+ channel (T-VGCC) enhancer with in vivo cognitive deficits-improving efficacy.
SAK3 is a potent and orally active spiroimidazopyridine derivative that enhances Cav3.1 and Cav3.3, but not Cav3.2, T-type voltage-gated Ca2+ channel (T-VGCC) activity (∼20% peak current increase with 0.1 nM SAK3 by whole-cell patch-clamp using human Cav3.1 or Cav3.3 transfected neuro2A; no effect up to 10 nM using Cav3.2 transfectant). Acute SAK3 oral administration (0.5 mg/kg) significantly enhances hippocampal CA1 region acetylcholine (ACh) release in naïve mice, as well as increases hippocampal ACh levels and improves memory deficits among olfactory-bulbectomized (OBX) mice. Daily SAK3 oral administration 24 hrs following hypothyroidism induction by methimazole (MMI) is efficacious against MMI-induced medial septum (MS) cholinergic neurons loss (0.5-1 mg/kg/day) and cognitive deficits (1 mg/kg/day).
Methimazole (MMI) is a first-line therapy used to manage hyperthyroidism and Graves' disease. Despite its therapeutic benefit, chronic MMI administration can lead to hypothyroidism and perturb brain homeostasis in patients, resulting in neuropsychiatric disorders such as depression and cognitive dysfunction.
Neurobiology of disease, 143, 105006-105006 (2020-07-06)
T-type calcium channels, in the central nervous system, are involved in the pathogenesis of many neurodegenerative diseases, including TAF1 intellectual disability syndrome (TAF1 ID syndrome). Here, we evaluated the efficacy of a novel T-type Ca2+ channel enhancer, SAK3 (ethyl 8'-methyl-2'
Neurobiology of disease, 149, 105224-105224 (2020-12-29)
The TATA-box binding protein associated factor 1 (TAF1) is part of the TFIID complex that plays a key role during the initiation of transcription. Variants of TAF1 are associated with neurodevelopmental disorders. Previously, we found that CRISPR/Cas9 based editing of
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